Our proposed Research Program Project (PPG): The SCRIPPS Research in-MethAmphetamine-NeuroAIDS Research Program (TSRI-MANARP) seeks to determine in select animal models, the neurotoxic infection with methamphetamine (METH) neuropharmacology. Using pre-clinical models (mice, felines and macaques), we will determine the location, biological course, and functional consequence of what we hypothesize to be common pathological processes leading to a more fulminant viral injection and functional decline in treated animals. We believe that only by employing the controlled experimental settings provided in the proposed experimental plan will the precise biological interactions and risk factors for pathology be discerned. Employing three well established animal models of neuro-AIDS we propose to investigate several methamphetamine neuropharmacology and NeuroAIDS-related neurotoxicity. Each animal model brings to convergence of these toxic phenotypes. Preliminary data included with the revised application provides new evidence for synergy in METH neuropharmacology and HIV-1 pathogenesis; evidence that is bolstered by theme to investigate the role of methamphetamine on disease progression and functional pathology in our documented high risk behaviors for HIV-1 exposure associated with methamphetamine abuse; 2. The converging evidence of both sub-cortical and cortical pathologies independently associated with both agents; 3. The evidence of direct actions of amphetamines on immune status, and 4. The woeful under representation of cellular, behavioral, and pathophysiological studies in this area.